The clinical impact of serum soluble CD25 levels in children with Langerhans cell histiocytosis.

OBJECTIVE: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm with inflammatory characteristics. This study aims to investigate the correlation between sCD25 levels and clinical characteristics, as well as prognosis, in pediatric LCH. METHODS: Serum sCD25 levels were measured in 370 LCH patients under 18 years old using ELISA assays. The patients were divided into two cohorts based on different treatment regimens. We further assessed the predictive value for the prognosis impact of sCD25 in a test cohort, which was validated in the independent validation cohort. RESULTS: The median serum sCD25 level at diagnosis was 3908 pg/ml (range: 231-44 000pg/ml). sCD25 level was significantly higher in multi-system and risk organ positive (MS RO+) LCH patients compared to single-system(SS) LCH patients (p < 0.001). Patients with elevated sCD25 were more likely to have involvement of risk organs, skin, lung, lymph nodes, or pituitary (all p < 0.05). sCD25 level could predict LCH progression and relapse, with an area under the ROC curve of 60.6 %. The optimal cutoff value was determined at 2921 pg/ml. Patients in the high-sCD25 group had significantly worse progression-free survival compared to those in the low-sCD25 group (p < 0.05). CONCLUSION: Elevated serum sCD25 level at initial diagnosis was associated with high-risk clinical features and worse prognosis. sCD25 level can predict the progression/recurrence of LCH following first-line chemotherapy.

Biomarkers in Pediatric Hemophagocytic Lymphohistiocytosis With Central Nervous System Involvement: A Cohort Study.

BACKGROUND: The aim of this study was to analyze the clinical significance of cerebrospinal fluid (CSF) cytokines in hemophagocytic lymphohistiocytosis associated with central nervous system (CNS-HLH). METHODS: CSF cytokine levels, including interferon (IFN)-γ, soluble CD25 (sCD25), interleukin (IL)-6, IL-10, IL-18, and CXCL9 were measured at disease onset and during the treatment. Five newly diagnosed patients with demyelination disease were enrolled for comparison. RESULTS: Sixty-five samples from 36 patients (13 in the CNS group and 23 in the non-CNS group) were detected. Levels of CSF IFN-γ, sCD25, IL-10, IL-18, and CXCL9 in the CNS group were higher than those in the non-CNS group (P=0.038, <0.001, <0.001, 0.005, and <0.001), and levels of CSF sCD25, IL-10, IL-18, and CXCL9 in the CNS group were higher than those in the demyelination group (P=0.001, 0.008, 0.004, and 0.003). There was no significant difference in IL-6 levels among the 3 groups (P=0.339). CSF IFN-γ, sCD25, IL-10, IL-18, and CXCL9 could assist in diagnosing CNS-HLH. The diagnostic efficiency of CSF sCD25, IL-10, and CXCL9 was better, with a cutoff value of 154.64, 1.655, and 19.54 pg/mL, respectively. The area under the curve was >0.9, with sensitivity and specificity >80%. Correlation analysis suggested that in the CNS group, IFN-γ levels in CSF and serum correlated positively (R=0.459, P=0.007), while there was no correlation between CSF CXCL9 and serum IFN-γ (P=0.915). CONCLUSIONS: CSF IFN-γ, sCD25, IL-10, IL-18, and CXCL9 levels were significantly higher in HLH patients with CNS involvement than those without and could predict HLH patients with CNS involvement. CSF CXCL9 might be a more sensitive biomarker to CNS-HLH than IFN-γ, while CSF IL-6 does not seem to play a vital role.

Clinical features and outcomes of 17 children with systemic juvenile xanthogranuloma (sJXG) including five complicated with hemophagocytic lymphohistiocytosis (HLH).

Juvenile xanthogranuloma (JXG) is primarily limited to the skin, and systemic JXG (sJXG) is rarely reported. Reports of sJXG patients with hemophagocytic lymphohistiocytosis (HLH) are particularly rare. Herein, we conducted a retrospective study of children diagnosed with sJXG in the Hematology Centre of Beijing Children's Hospital from Jan. 2016 to Dec. 2021. The clinical features, laboratory parameters, treatments and outcomes of 17 sJXG patients were investigated, including five complicated with HLH. All sJXG-HLH patients had intermittent fever, rash, hepatosplenomegaly, cytopenia and high levels of soluble CD25, but interferon-γ was almost normal. Patients with sJXG-HLH had a younger diagnosis age (P = 0.035) and were more likely to have skin, liver, and spleen involvement than those without HLH (P = 0.029, P = 0.003, P = 0.003, respectively). Corticosteroids and/or ruxolitinib could be used to control the hyperinflammatory status when HLH was diagnosed. The treatment of sJXG varied, including Langerhans cell histiocytosis (LCH)-based chemotherapy and targeted therapy. The overall response rate of sJXG for first-line and second-line chemotherapy was 50.0% (5/10) and 50% (4/8), respectively. Patients with BRAF V600E mutation showed a response to dabrafenib. There was no significant difference in the overall survival and progression-free survival between sJXG patients without and with HLH (P = 0.12 and P = 0.46, respectively). Therefore, LCH-based chemotherapy could serve as an effective treatment for sJXG patients, and dabrafenib, to some extent, showed efficacy in controlling sJXG in patients with BRAF V600E mutation. The prognosis of sJXG-HLH patients seemed to be comparable to patients without HLH.

Clinical Characteristics of Peripheral Lymphocyte Subtypes in Chronic Active Epstein-Barr Virus Infection.

BACKGROUND: We aimed to analyze the clinical characteristics of peripheral Epstein-Barr virus (EBV)-infected lymphocyte subtypes in children with chronic active EBV infection (CAEBV). METHODS: The levels of peripheral EBV infection of CD4+ T cells, CD8+ T cells, and CD56+ natural killer (NK) cells were determined by flow cytometry and quantitative polymerase chain reaction (qPCR) in patients with CAEBV from July 2017 to July 2022. RESULTS: In total, 112 children with CAEBV were evaluated. Of these, CD4+ type, CD8+ type, and CD56+ type were defined in 44, 21, and 47 patients, respectively. Patients with CD8+ T-cell type had a significantly higher frequency of rash, while hepatomegaly was more common in patients with CD4+ T-cell type. Generally, patients with CD8+ T-cell type had the lowest overall survival rate (P = .017). Patients treated with chemotherapy and hematopoietic stem cell transplantation (HSCT) had a better prognosis (P = .001). In multivariate analysis, rash, hemophagocytic lymphohistiocytosis, CD8+ T-cell type, and no decrease of plasma EBV-DNA after treatment were independent indicators of poor prognosis (P = .002, .024, .022, and .012, respectively). CONCLUSIONS: In children with CAEBV, rash was more frequent in patients with CD8+ T-cell type, whereas patients with CD4+ T-cell type were more likely to develop hepatomegaly. Patients with CD8+ T-cell type had a poor prognosis despite receiving chemotherapy or further HSCT.

Ruxolitinib Monotherapy for a Child With HAVCR2 Gene Mutation Associated Subcutaneous Panniculitis-like T-cell Lymphoma: A Case Report.

BACKGROUND: The occurrence of hemophagocytic lymphohistiocytosis (HLH) in patients with subcutaneous panniculitis-like T-cell lymphoma (SPTCL) may be due to HAVCR2 gene mutation, leading to T-cell immunoglobulin and mucin domain-containing molecule 3 deficiency, T-cell and macrophage activation, and proinflammatory cytokine production. OBSERVATION: We report a patient with SPTCL and HLH for whom ruxolitinib, used as a novel treatment, showed notable therapeutic effects. CONCLUSIONS: Remission of both HAVCR2 mutation-induced high inflammatory characteristics and significant symptoms post-ruxolitinib administration suggested that patients with SPTCL and HLH may not represent typical lymphoma cases. Ruxolitinib, with its relatively low toxic side effects, can provide favorable outcomes.

Genetic Landscape and Its Prognostic Impact in Children With Langerhans Cell Histiocytosis.

CONTEXT.­: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm that predominantly affects young children. OBJECTIVE.­: To investigate genetic alterations and their correlation with clinical characteristics and prognosis in pediatric LCH. DESIGN.­: We performed targeted sequencing to detect mutations in LCH lesions from pediatric patients. RESULTS.­: A total of 30 genomic alterations in 5 genes of the MAPK pathway were identified in 187 of 223 patients (83.9%). BRAF V600E (B-Raf proto-oncogene, serine/threonine kinase) was the most common mutation (51.6%), followed by MAP2K1 (mitogen-activated protein kinase kinase 1) alterations (17.0%) and other BRAF mutations (13.0%). ARAF (A-Raf proto-oncogene, serine/threonine kinase) and KRAS (KRAS proto-oncogene, GTPase) mutations were relatively rare (2.2% and 0.9%, respectively). Additionally, FNBP1 (formin-binding protein 1)::BRAF fusion and MAP3K10 (mitogen-activated protein kinase kinase 10) mutations A17T and R823C were identified in 1 case each, with possible constitutive activation of ERK1/2 phosphorylation. BRAF V600E was more frequent in patients with risk organ involvement, while MAP2K1 mutation was more prevalent in patients with single-system LCH (P = .001). BRAF V600E was associated with craniofacial bone, skin, liver, spleen, and ear involvement (all P < .05). Patients with other BRAF mutations had a higher proportion of spinal column involvement (P = .006). Univariate analysis showed a significant difference in progression-free survival among the 4 molecular subgroups for patients treated with first-line therapy (P = .02). According to multivariate analysis, risk organ involvement was the strongest independent adverse prognostic factor (hazard ratio, 8.854; P < .001); BRAF or MAP2K1 mutation was not an independent prognostic factor. CONCLUSIONS.­: Most pediatric patients with LCH carry somatic mutations involving the MAPK pathway, correlating with clinical characteristics and outcomes for first-line chemotherapy.

Clinical features and treatment outcomes of liver involvement in paediatric Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder in children, and liver involvement in LCH is rare. This retrospective study reported the clinical features and prognosis of patients with hepatic LCH. Liver involvement was defined by histopathological findings, liver dysfunction or abnormalities, or ultrasound imaging. A total of 130 patients (14.5%) with hepatic LCH out of 899 in the LCH population were enrolled. Patients with liver involvement had greater frequencies of skin, lung, hearing system, and haematologic system involvement, and hemophagocytic lymphohistiocytosis (P<0.001, 0.001, 0.002, 0.009, and <0.001, respectively). Overall survival and progression-free survival were lower in LCH patients with liver involvement than in those without liver involvement (P<0.001 and <0.001). In patients with liver involvement, the overall survival (OS) and progression-free survival (PFS) rates were lower in patients with cholangitis than in those without cholangitis (P<0.020 and 0.030). For the treatment response, the response rate of hepatic LCH patients to initial first-line therapy (n=89) was 22.5%. However, there was no significant difference in the response rate or recurrence rate between patients who shifted from first-line treatment to second-line treatment (n=29) or to targeted therapy (n=13) (P=0.453 and 1.000). The response rate of hepatic LCH patients who received initial second-line therapy (n=13) was 38.5%. Two of these patients subsequently experienced bone recurrence. The response rate of hepatic LCH patients who received initial targeted therapy (n=16) was 75.0%. Three patients subsequently experienced recurrence, including 2 in the bone and 1 in the liver and skin. A total of 39.3% of patients who received second-line treatment had severe myelosuppression (grade III-IV), and 50.8% had varying degrees of gastrointestinal events, whereas there was no severe toxicity in patients who received first-line treatment and targeted therapy. Four patients underwent liver transplantation because of liver cirrhosis. The patients' liver disease improved within a follow-up period of 18-79 months. This study demonstrated that LCH with liver involvement, especially cholangitis, indicates a poor prognosis. Targeted therapy provides a good treatment response and less toxicity. However, it may relapse after withdrawal. Liver transplantation is still a reliable salvage option for patients with end-stage liver disease.

Molecular Engineering to Regulate the Pseudo-Graphitic Structure of Hard Carbon for Superior Sodium Energy Storage.

Resin-derived hard carbons have shown great advantages in serving as promising anode materials for sodium-ion batteries due to their flexible microstructure tunability. However, it remains a daunting challenge to rationally regulate the pseudo-graphitic crystallite and defect of hard carbon toward advanced sodium storage performance. Herein, a molecular engineering strategy is demonstrated to modulate the cross-linking degree of phenolic resin and thus optimize the microstructure of hard carbon. Remarkably, the resorcinol endows resin with a moderate cross-linking degree, which can finely tune the pseudo-graphitic structure with enlarged interlayer spacing and restricted surface defects. As a consequence, the optimal hard carbon delivers a notable reversible capacity of 334.3 mAh g-1 at 0.02 A g-1, a high initial Coulombic efficiency of 82.1%, superior rate performance of 103.7 mAh g-1 at 2 A g-1, and excellent cycling durability over 5000 cycles. Furthermore, kinetic analysis and in situ Raman spectroscopy are performed to reveal the electrochemical advantage and sodium storage mechanism. This study fundamentally sheds light on the molecular design of resin-based hard carbons to advance sodium energy for scale-up applications.

The plasma-soluble CSF1R level is a promising prognostic indicator for pediatric Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare hematologic neoplasm characterized by the clonal proliferation of Langerhans-like cells. Colony-stimulating factor 1 receptor (CSF1R) is a membrane-bound receptor that is highly expressed in LCH cells and tumor-associated macrophages. In this study, a soluble form of CSF1R protein (sCSF1R) was identified by plasma proteome profiling, and its role in evaluating LCH prognosis was explored. We prospectively measured plasma sCSF1R levels in 104 LCH patients and 10 healthy children using ELISA. Plasma sCSF1R levels were greater in LCH patients than in healthy controls (p < .001) and significantly differed among the three disease extents, with the highest level in MS RO+ LCH patients (p < .001). Accordingly, immunofluorescence showed the highest level of membrane-bound CSF1R in MS RO+ patients. Furthermore, the plasma sCSF1R concentration at diagnosis could efficiently predict the prognosis of LCH patients treated with standard first-line treatment (AUC = 0.782, p < .001). Notably, dynamic monitoring of sCSF1R levels could predict relapse early in patients receiving BRAF inhibitor treatment. In vitro drug sensitivity data showed that sCSF1R increased resistance to Ara-C in THP-1 cells expressing ectopic BRAF-V600E. Overall, the plasma sCSF1R level at diagnosis and during follow-up is of great clinical importance in pediatric LCH patients.

Creating A child-friendly social environment for fewer conduct problems and more prosocial behaviors among children: A LASSO regression approach.

BACKGROUND: Creating a child-friendly social environment is an important component of promoting child-friendly city development. This study aims to explore the key indicators of friendly family, school and community social environments from the perspective of children's conduct problems and prosocial behaviors. METHOD: The sample included grade 3-5 students from one public elementary school in the urban areas and another public elementary school in the rural areas of a Chinese city pursuing a child-friendly philosophy. A total of 418 participants were included in this study. Data on conduct problems, prosocial behaviors and the social environment were collected. To effectively select important variables and eliminate estimation bias, this study used LASSO regression to identify key indicators predicting children's conduct problems and prosocial behavior, followed by linear regression coefficient estimation and significance testing. RESULTS: Creating a friendly family environment (ensuring family members' assistance with academic problems) and school environment (reducing cheating, fighting, and unfriendly teacher language) was associated with reduced conduct problems in children. Creating a positive family atmosphere (enhancing children's trust in family members), school environment (increasing parents' awareness of school affairs, reinforcing students' prosocial behavior, increasing extracurricular activity programs, and encouraging student engagement in academics) and community environment (respecting all children in the community) was associated with improving children's prosocial behavior. CONCLUSIONS: This study transforms the multidimensional, complex child-friendly social environment evaluation indicator system into concise and specific measurement indicators, which can provide theoretical and practical implications for government decision-making in child-friendly city development through empirical research.

Treatment of children with refractory/relapse high risk langerhans cell histiocytosis with the combination of cytarabine, vindesine and prednisone.

BACKGROUND: The patients with multisystem and risk organ involvement Langerhans cell histiocytosis (MS-RO + LCH) have poor prognosis. The patients with MS-LCH who failed front-line therapy have a high mortality rate and the standard salvage treatment has not been established. The combination of cytarabine (Ara-c), vincristine (VCR) and prednisone might be effective for refractory/relapse MS-RO + LCH, with low toxicity. METHODS: We retrospectively analyzed pediatric refractory/relapse MS-RO + LCH patients treated with the low-dose Ara-c (100mg/m2/d×5days) or high-dose Ara-c (500mg/m2/d×5days) combined with vindesine (VDS) and prednisone in a single center. The efficacy, outcomes and adverse events were analyzed. RESULTS: From January 2013 to December 2016, 13 patients receiving the low-dose Ara-c chemotherapy (LAC) and 7 patients receiving the high-dose Ara-c chemotherapy (HAC) were included in the study. 11 (84.6%) of the 13 patients treated with the LAC regimen and 6 (85.7%) of the 7 patients treated with the HAC regimen had response after four courses of the therapy. All patients in the study were alive during follow-up and the 3-year event-free survival rate (EFS) was 53.7% and 85.7% in the LAC and HAC groups. The most frequent adverse event was Grade 1/2 myelosuppression, which was observed in 38.5% (5/13) and 42.9% (3/7) of the patients receiving the LAC and HAC regimen. CONCLUSIONS: A combination of Ara-c, VDS and prednisone was effective and safe for some patients with refractory/relapse MS-RO + LCH. The high-dose Ara-c regimen was associated with a numerically higher EFS rate.

Ruxolitinib-based regimen in children with primary hemophagocytic lymphohistiocytosis.

Primary hemophagocytic lymphohistiocytosis (pHLH) is a rare immune disorder and hematopoietic stem cell transplan- tation (HSCT) is the only potentially curative treatment. Given the high pre-HSCT mortality of pHLH patients reported in the HLH-2004 study (17%), more regimens to effectively control the disease and form a bridge with HSCT are needed. We conducted a retrospective study of pHLH children treated by ruxolitinib (RUX)-based regimen. Generally, patients received RUX until HSCT or unacceptable toxic side-effect. Methylprednisolone and etoposide were added sequentially when the disease was suboptimally controlled. The primary end point was 1-year overall survival. Twenty-one pHLH patients (12 previously treated and 9 previously untreated) were included with a median follow-up of 1.4 years. At last follow-up, 17 (81.0%) patients were alive with a 1-year overall survival of 90.5% (95% confidence interval: 84.1-96.9). Within the first 8 weeks, all patients had an objective response, of which 19 (90.5%) achieved complete response (CR) and two (9.5%) achieved partial response (PR) as a best response. Seventeen (81.0%) patients received HSCT, of which 13 (76.5%) had CR, three (17.6%) had PR and one (5.9%) had disease reactivation at the time of HSCT. Fifteen (88.2) patients were alive post- HSCT. Notably, eight (38.1%) patients received zero doses of etoposide, suggesting the potential of RUX-based regimen to reduce chemotherapy intensity. Patients tolerated RUX-based regimen well and the most frequently observed adverse events were hematologic adverse events. Overall, RUX-based regimen was effective and safe and could be used as a bridge to HSCT for pHLH children.

Genetic and clinical characteristics of primary hemophagocytic lymphohistiocytosis in children.

To analyze the genetic variation and prognosis of primary hemophagocytic lymphohistiocytosis (pHLH) in children and the clinical features of isolated central nervous system HLH (CNS-HLH). We retrospectively analyzed the clinical and genetic data of 480 HLH children admitted to our hospital from September 2017 to September 2022. There were 66 patients (13.75%) with pHLH, and the median age was 3.21 years (0.17-12.92 years). Variants in UNC13D (22/66, 33.33%), PRF1 (20/66, 30.30%) and XIAP (11/66, 16.67%) were the most common. More CNS involvement was observed in pHLH patients than in secondary hemophagocytic lymphohistiocytosis (sHLH) patients (50% vs. 25.3%, P = 0.001). Eight pHLH patients had isolated CNS-HLH at onset, which progressed to systemic HLH within 10-30 days to several years. Among them, five patients who underwent hematopoietic stem cell transplantation (HSCT) survived without CNS sequelae, and the three patients who did not undergo HSCT died of disease progression or recurrence. Determination of natural killer (NK) cell cytotoxicity and CD107a levels had low sensitivity and specificity in the diagnosis of pHLH, especially in patients with PRF1 and XIAP mutations. The 3-year overall survival (OS) was significantly lower in pHLH patients than in sHLH patients (74.5% ± 14.7% vs. 89.2% ± 3.53%, P = 0.021) and in patients with CNS involvement than in those without (53.8% ± 26.07% vs. 94.4% ± 10.58%, P = 0.012). There was a significant difference in OS among pHLH patients with different gene variants (P = 0.032); patients with PRF1 variants had poor 3-year OS, and patients with XIAP variants had good 3-year OS (50% ± 28.22% and 100%, respectively). pHLH patients with distinct variants have different prognoses. Isolated CNS-HLH patients are easily misdiagnosed, and HSCT may be beneficial for these patients. Determination of NK cell cytotoxicity and CD107a levels cannot precisely distinguish pHLH from sHLH.

Resolving Deactivation of Low-Spin Fe Sites by Redistributing Electron Density toward High-Energy Sodium Storage.

Prussian blue (PB) has been an emerging class of cathode material for sodium-ion batteries due to its low cost and high theoretical capacity. However, their working voltage and capacity are substantially restricted due to the deactivation of low-spin Fe sites. Herein, we demonstrate a universal strategy to activate the low-spin Fe sites of PB by hybridizing them with the π-π conjugated electronic conductors. The redistribution of electron density between π-π conjugated conductors and PB effectively promotes the participation of low-spin Fe sites in sodium storage. Consequently, the low-spin Fe-induced plateau is greatly aroused, resulting in a high specific capacity of 148.4 mAh g-1 and remarkable energy density of 444.2 Wh kg-1. In addition, the excellent structural stability enables superior cycling stability over 2500 cycles and outstanding rate performance. The work will provide fundamental insight into activating the low-spin Fe sites of PB for advanced battery technologies.

Clinical characteristics of peripheral lymphocyte subtypes in chronic active Epstein-Barr virus infection.

PURPOSE: To analyze the clinical characteristics of peripheral Epstein-Barr virus(EBV)-infected lymphocyte subtypes in children with chronic active EBV infection(CAEBV). METHODS: The levels of peripheral EBV infection of CD4 + T cells, CD8 + T cells, and CD56 + NK cells were determined by flow cytometry and qPCR in patients with CAEBV from July 2017 to July 2022. RESULTS: A total of 112 children with CAEBV were evaluated in the study. Of them, CD4 + type, CD8 + type, and CD56 + type were defined in 44, 21, and 47 patients, respectively. Patients with CD8 + T-cell type had a significantly higher frequency of rash, while hepatomegaly was more common in patients with CD4 + T-cell type. Generally, patients with CD8 + T-cell type had the lowest overall survival(OS) rate(P = 0.017). As for treatment, patients treated with chemotherapy and hematopoietic stem cell transplantation had a better prognosis(P = 0.001). In multivariate analysis, rash, HLH, CD8 + T-cell type, and no decrease of plasma EBV-DNA after treatment were indicated as independent factors of poor prognosis(P = 0.002, 0.024, 0.022, and 0.012, respectively). CONCLUSION: In children with CAEBV, the rash was more frequent in patients with CD8 + T-cell type, whereas patients with CD4 + T-cell type were more likely to develop hepatomegaly. Patients with CD8 + T-cell type had a poor prognosis despite receiving chemotherapy or further HSCT.

Subcutaneous panniculitis-like T-cell lymphoma associated with hemophagocytic lymphohistiocytosis: a systematic review of 63 patients reported in the literature.

To review and summarize the clinical features, treatment strategies, and prognosis of subcutaneous panniculitis-like T-cell lymphoma complicated with hemophagocytic lymphohistiocytosis (SPTCL-HLH). We searched the Web of Science, Embase, Cochrane Library, and PubMed databases. The keywords were subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis or hemophagocytic syndrome. The patients were divided into a mutated group and a wild-type group based on the existence of HAVCR2 gene mutation. A total of 45 reports, including 63 patients with SPTCL-HLH, were included in the systematic review. Twelve patients detected gene mutations, including 11 with the HAVCR2 gene mutation and 1 with the STXBP2 gene mutation. Thirty-one patients were tested for autoantibodies. Compared with the wild-type group, patients in the mutated group were younger (p = 0.017), and the autoantibody-positive rate was higher (p = 0.006). The main treatment target of 17 patients was to control HLH, yielding an ORR of 88.2%. Two cases relapsed, and both were treated with corticosteroid monotherapy. The corticosteroid monotherapy experienced a higher recurrence rate than the corticosteroids plus other immunoregulatory agents therapy (66.7 vs. 0.0%, p = 0.029). Eighteen patients received initial anthracycline-based chemotherapy, and 50.0% reached remission. The ORR of initial chemotherapy aiming at controlling HLH was higher than those of anthracycline-based chemotherapy (p = 0.015). The ORR was higher in patients initially controlled for HLH versus chemotherapy without HLH control first (90.5 vs. 61.5%, p = 0.024). Interestingly, one patient with juvenile idiopathic arthritis developed SPTCL-HLH during tocilizumab therapy, discontinuing tocilizumab led to a remission of the disease spontaneously. Sixteen patients received stem cell transplantation (SCT). Fifteen patients, including 5 with relapsed/refractory SPTCL-HLH, responded well and survived after receiving SCT. One case who received a sibling-identical SCT relapsed. Further analysis revealed a homozygous HAVCR2 mutation with the donor. The 2-year overall survival (OS) was 91.0% ± 4.4%. There was a significant difference in the OS among patients of different age groups, and patients aged 40-60 had the lowest 2-year OS (66.7% ± 19.2%). Patients with HAVCR2 gene mutations are younger and more likely to be misdiagnosed with autoimmune diseases. Initial treatment of corticosteroids plus immunoregulatory agents attaches great significance to avoiding too aggressive therapies. Intensive anthracycline-based chemotherapy such as CHOP or CHOP-like regimens can also induce long-term remission for aggressive disease. SCT is still a reliable strategy currently. In addition, a watch and wait approach is recommended in patients with mild SPTCL-HLH caused by drugs. The occurrence of HLH does not necessarily mean a more rapidly progressive disease and worse prognosis in patients with SPTCL, but older patients with SPTCL-HLH may be associated with a lower survival rate.

Optical micro mechanical accelerometer with double grating: design and simulation.

A double-grating-based optical micro mechanical accelerometer with differential detection structure is reported in order to enhance the optical scale factor. A theoretical model is established based on the multi-slits Fraunhofer diffraction model. According to the calculation and analysis, the normalized optical scale factor is improved from 5.491E6 with the single-side detection structure to 10.98E6 with the differential detection structure. Mechanical sensitivity with 4.04 nm/g and natural frequency with 7756.8 Hz of the optical accelerometer are shown by finite element simulation. The results of simulations show a novel scheme for an optical micro mechanical accelerometer with high resolution, to the best of our knowledge. Furthermore, micro-opto-electro-mechanical system fabrication flow is given in this work, which provides a reference for other kinds of optical sensors.

Cladribine and cytarabine in children refractory high risk multisystem Langerhans cell histiocytosis.

There is no uniform regimen for refractory Langerhans cell histiocytosis (LCH). We retrospectively described patients with refractory multisystem and risk organ involvement LCH treated with the low-dose (Ara-c, 100 mg/m2/d × 5day; 2-CDA, 5 mg/m2/d × 5day) chemotherapy (LDC) and the intermediate-dose (Ara-c, 500 mg/m2/d × 5day; 2-CDA, 9 mg/m2/d × 5day) chemotherapy (IDC). 26 patients and 10 patients receiving the LDC and IDC regimen from January 2013 to December 2016 were included in the study. The overall response rate exhibited no significant difference between the LDC and IDC groups after four courses (76.9% vs 90%, P = 0.375) and eight courses (80.8% vs 100%, P = 0.135) of treatment. No statistical differences in the overall survival rate were observed between the two groups, but 5-year event-free survival rate of patients in the IDC group was higher than that in the LDC group at the median follow-up of 6.16 and 5.07 years (88.9% vs 52.9%, P = 0.033). The patients in the IDC group had more severe myelosuppression than those in the LDC group (grade 3/4 myelosuppression, 80% vs 19.2%, P = 0.001). The intermediate-dose regimen of 2CDA and Ara-c had a higher event-free survival rate and a similar overall survival rate compared with the low-dose regimen.

Highly reproducible and cost-effective one-pot organoid differentiation using a novel platform based on PF-127 triggered spheroid assembly.

Organoid technology offers sophisticatedin vitrohuman models for basic research and drug development. However, low batch-to-batch reproducibility and high cost due to laborious procedures and materials prevent organoid culture standardization for automation and high-throughput applications. Here, using a novel platform based on the findings that Pluronic F-127 (PF-127) could trigger highly uniform spheroid assembly through a mechanism different from plate coating, we develop a one-pot organoid differentiation strategy. Using our strategy, we successfully generate cortical, nephron, hepatic, and lung organoids with improved reproducibility compared to previous methods while reducing the original costs by 80%-95%. In addition, we adapt our platform to microfluidic chips allowing automated culture. We showcase that our platform can be applied to tissue-specific screening, such as drug toxicity and transfection reagents testing. Finally, we generateNEAT1knockout tissue-specific organoids and showNEAT1modulates multiple signaling pathways fine-tuning the differentiation of nephron and hepatic organoids and suppresses immune responses in cortical organoids. In summary, our strategy provides a powerful platform for advancing organoid research and studying human development and diseases.